A key question in attempts to understand brain function is how does the electrical activity of neurons give rise to specific perceptions or memories? What is the neural representation of the external world or of past events? While there is a basic understanding of brain circuits at the macroscopic level between defined anatomical regions and to a lesser extent locally within brain regions, there are currently no techniques that allow the identification or manipulation of neuronal ensembles that represent a specific external stimulus or event. The primary goal of this proposal is to improve and extend upon a genetic approach that we have developed that uses the cfos promoter and the tetracycline system to allow the introduction of long lasting genetic tags into active neuronal ensembles (Reijmers et al. 2007; Matsuo et al. 2008). We will develop and validate transgenic mouse lines that allow the direct electrical and biochemical manipulation of environmentally activated neuronal ensembles. If successful, these mice will provide a tool that should be generally useful throughout a wide range of neuroscience disciplines. PUBLIC HEALTH RELEVANCE: The human mind is made up of specific bits of knowledge and memories that are integrated within a relational network. Many neurological and neuropsychiatric disorders lead to a disruption of memories or of the cognitive framework in which these memories exists. In this proposal we develop mouse models that allow us to genetically alter, and thus manipulate electrically and molecularly, neurons that make up specific memories. These tools should be useful in dissecting the underlying circuit structure of specific memories, how they are accessed, and how they are disrupted in disease models.